Journal of Experimental Pharmacology最新文献

Introduction/background: Exposure to heavy metals like cadmium can adversely affect our brain function and cognitive abilities. Scientific evidence has strongly linked cadmium exposure to neurotoxicity, including oxidative damage and neuroinflammation. This study investigated the therapeutic role of Zingerone on cadmium-induced inflammation, oxidative stress and cognitive decline in the prefrontal cortex.

Methodology: Thirty adult male Wistar rats were randomly assigned to six groups of five rats each. Group A (Control group), Group B (5mg/kg of cadmium induction), Group C (100mg/kg of Zingerone only), Group D-F (Treatment groups: 5mg/kg of cadmium+50mg/kg,100mg/kg, 200mg/kg of Zingerone respectively). To determine the cognitive abilities, we used a novel object recognition test (NORT), the whole treatment lasted for 21 days. We used blood samples and brain tissue for histological, biochemical and immunohistochemical evaluations. Data from this study was analysed using GraphPad Prism 10, and statistical difference between groups was determined using one-way ANOVA followed by Tukey's post hoc test (p <0.05).

Result and discussion: There was significant reduction in superoxide dismutase (SOD), catalase (CAT) and significant increase malondialdehyde (MDA) in the cadmium-only group; however, this effect was mitigated in Groups C-F that received zingerone treatment. Cadmium exposure resulted in elevated levels of inflammatory cytokine Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-α), these increases were significantly reduced in all Zingerone-treated groups. Zingerone considerably improved cognitive function, as seen by significant improvements in the discrimination index and novel object recognition time. Also, Zingerone significantly mitigated the over-expressivity of astrocytes in the prefrontal cortex and improved the histoarchitecture of the prefrontal cortex.

Conclusion: This study shows that zingerone demonstrated anti-oxidative and anti-inflammatory abilities and enhanced cognitive performance. These results indicate that zingerone might be a useful therapeutic agent that can mitigate neuroinflammation, oxidative damage, and cognitive decline.

Introduction: Neurodegenerative diseases are a major public health concern, often associated with motor and cognitive deficits. Methamphetamine (METH) exposure induces lasting neurological impairment and neuronal loss. This study evaluated Morin's potential to reverse these effects, focusing on motor and cognitive dysfunction in METH-induced neurotoxicity.

Methods: Adult rats were randomly assigned into seven groups, including control, Morin-only, METH-only, METH plus fluoxetine, and three groups receiving METH followed by varying doses of Morin. Following METH induction, Morin, a natural flavonoid with antioxidant properties, was administered to rats. Neurobehavioral tests evaluated motor and cognitive function; serum levels of oxidative stress markers, inflammatory cytokines, dopamine, and acetylcholine were measured. Histological and immunohistochemical analyses of the basal ganglia were performed to evaluate neuronal integrity.

Results: METH exposure significantly elevated oxidative stress and inflammatory markers, altered neurotransmitter levels, and impaired both motor and cognitive performance, coinciding with neuronal loss in the basal ganglia. Treatment with Morin ameliorated these effects in a dose-dependent manner. Neuronal degenerative features noted in the METH-only group were significantly ameliorated in the Morin-treated groups.

Conclusion: These findings indicate that Morin mitigates METH-induced neurotoxicity by reducing oxidative stress, and suppressing inflammation. This study demonstrates Morin's potential as a treatment option for the neurological effects of methamphetamine misuse.

Background: In rural areas of KwaZulu-Natal and Eastern Cape Provinces, South Africa, women have traditionally used bark extracts from Cassipourea flanaganii, C. malosana, and C. gummiflua for skin lightening and sun protection. This study investigates the anti-tyrosinase and antioxidant activities of methanolic bark extracts from these species, aiming to validate their traditional use and identify potential lead compounds for the treatment of skin hyperpigmentation.

Methods: Anti-tyrosinase activity was evaluated using half-maximal inhibitory concentration (IC₅₀) values, and antioxidant capacity was measured through FRAP, DPPH, and TEAC assays. Polyphenol and flavanol contents were quantified using Folin-Ciocalteu method. Potential lead compounds were identified through molecular docking, pharmacokinetic analysis, and molecular dynamics (MD) simulations. Statistical analyses, including ANOVA and post-hoc tests, compared extract activities.

Results: C. flanaganii exhibited the most potent anti-tyrosinase activity (IC₅₀: 37.10 µg/mL), though statistical differences among species were non-significant. C. gummiflua showed the highest polyphenol (143.68 mg GAE/g) and flavanol (14.67 mg QE/g) content, correlating with superior antioxidant activity (FRAP: 526.07 µmol AAE/g; DPPH: 390.26 µmol TE/g; TEAC: 596.98 µmol TE/g). The isolated compound 7-methoxygeranin A demonstrated lower anti-tyrosinase activity (IC₅₀: 45.16 µg/mL) compared to C. flanaganii extract, suggesting the presence of more potent metabolites. Molecular docking and MD simulations identified emodin 6,8-dimethyl ether as a thermodynamically stable lead compound (binding free energy: -39.88 kcal/mol), interacting with key catalytic residues over 150 ns. The compound demonstrated prolonged residence at the active site of tyrosinase, indicating strong-binding stability.

Conclusion: While C. flanaganii demonstrated the strongest anti-tyrosinase activity, C. gummiflua showed the highest antioxidant potential. Emodin 6,8-dimethyl ether emerged as a promising candidate for skin-lightening applications, warranting further in vitro and in vivo validation. These findings support the traditional use of Cassipourea species and highlight their potential for developing natural skin health products. Further studies are needed to explore the pharmacokinetics, safety, and efficacy of these compounds in clinical settings.

Purpose: Information on metal-organic frameworks (MOFs) as topical drug delivery systems (DDS) for antileishmanial drugs is limited. This study outlines our strategies for developing MOF-drug conjugate as a topical treatment for cutaneous leishmaniasis (CL) in mice infected with Leishmania (L). amazonensis.

Methods: We selected conjugates from two commercial MOFs (ZIF-8 and Fe-BTC) and seven antileishmanial compounds. Amphotericin B (AmB) and zeolitic imidazolate framework-8 (AmB@ZIF-8) were chosen and prepared at an AmB: ZIF-8 ratio of 1.5:1.0 using the impregnation method. Conjugates were characterised using dynamic light scattering, UV-Vis, FTIR, and SEM. Hydrogels were prepared and evaluated for toxicity and efficacy in CL-BALB/c mice.

Results: AmB@ZIF-8 exhibited a 59.6% loading capacity, 6.67% encapsulation efficiency, and 2% in vitro drug release (IVR). The particle size of AmB@ZIF-8 was smaller and more polydisperse than ZIF-8 (1370 nm vs 2537 nm). The conjugation of AmB to ZIF-8 was demonstrated. AmB@ZIF-8 exhibited similar antileishmanial activity to AmB against promastigotes. Topical 0.5% AmB@ZIF-8 and 0.5% AmB hydrogels, administered for 30 days, were unable to decrease lesion sizes or parasite loads. Initially, there was stabilisation of the lesion size; however, the lesions subsequently increased considerably during the 30-day follow-up period. The MOF-hydrogel treatment was non-irritating.

Conclusion: There were very low EE% and AmB IVR. AmB@ZIF-8 and AmB hydrogels were found to be safe but ineffective against CL-infected mice. Several factors may explain these negative results, including the large size of the commercial ZIF-8, the aggregation of AmB in solution, the excess AmB used for impregnation, and the conditions of the IVR assay. We suggest continuing to use ZIF-8 as a DDS due to its sensitivity to acidic pH levels; however, we recommend reducing the particle size and lowering the drug-to-ZIF-8 ratio. Other alternatives are discussed in the present paper. We also advocate investigating alternative antileishmanial drugs as cargo, such as miltefosine or pentamidine.

Introduction: RNA interference (RNAi) therapy represents an evolving advancement in the management of dyslipidemia. One prominent form of RNAi therapy is small interfering RNA (siRNA), which has emerged as a promising therapeutic strategy. This study aims to critically analyze the efficacy and safety of siRNA in the treatment of dyslipidemia.

Methods: PubMed, Scopus, and Web of Science servers were used to conduct a systematic search in compliance with the PRISMA guidelines.

Results: A total of 20 studies with 6651 participants were included in the analysis. The drugs used in the studies were. Inclisiran led to a notable 44.09% reduction in LDL and 37.5% in apolipoprotein levels among individuals with hypercholesterolemia. In hyperlipoproteinemia(a), therapies like Lepodisiran and Olpasiran achieved a 75.69% drop in apolipoproteins and 16.25% in LDL. For hypertriglyceridemia, agents such as ARO-APOC3 and Plozasiran showed over 50% reductions in both VLDL and triglycerides. In mixed hyperlipidemia and chylomicronemia, Plozasiran significantly reduced triglycerides by up to 79% and apolipoproteins by 87.5%. The 5 most common adverse effects reported were nasopharyngitis, diabetes mellitus (including new-onset diabetes mellitus and worsening diabetes mellitus), injection site adverse effects, back pain, and hypertension.

Conclusion: In conclusion, the benefits of siRNA therapy in dyslipidemia management appear to outweigh its potential drawbacks, demonstrating promising efficacy and safety profiles. However, further research is necessary to fully understand its long-term effects and optimize its therapeutic potential.

Purpose: This study aimed to explore the effect of Aaptamine, an alkaloid derived from marine sponges, on the vimentin expression in both mRNA and protein levels and the migration capacity of breast cancer cells.

Methods: The triple-negative breast cancer cell line MDA-MB-231 was used for in vitro experiments. Low-cytotoxicity concentrations of Aaptamine (12.5 to 50 μM) were given to MDA-MB-231 cells. The vimentin mRNA and protein expression were evaluated using RT-qPCR and immunofluorescence, respectively, 72 h after Aaptamine treatment. The migration scratch assay was conducted for 48 hours.

Results: Aaptamine treatment in three different doses did not affect the expression of vimentin at the mRNA level while significantly lowering vimentin protein expression at the concentration of 12.5 µM. In addition, Aaptamine significantly inhibited breast cancer cell migration in a dose-dependent manner.

Conclusion: Aaptamine inhibits vimentin protein expression and demonstrates anti-migration activity in the sub-cytotoxic dose.

Introduction: Diabetes mellitus, characterized by chronic hyperglycaemia, remains a major global health burden. Limitations of conventional therapies have led to growing interest in medicinal plants like Sclerocarya birrea (A. Rich.) Hochst. widely used in African ethnomedicine. Though prior research has focused more on the stem bark, studies on the leaves, considered more sustainable and traditionally relevant, are still lacking in vivo data. This study assessed the antidiabetic potential of a hydroethanolic leaf extract of Sclerocarya birrea in Wistar rats.

Methods: The extract was tested at 25-200 mg/kg in an oral glucose tolerance test (OGTT), and at 100-400 mg/kg in normoglycemic and high fructose-fed, streptozotocin (STZ)-induced type 2 diabetic rats over 21 and 28 days, respectively. Fasting blood glucose, insulin, glycated haemoglobin (HbA1c), glucose transporter type 4 (GLUT4), haematological and biochemical parameters, and histopathological changes in key organs were evaluated.

Results: In the OGTT, the extract significantly reduced postprandial blood glucose at 100 and 200 mg/kg starting from 60 minutes post-glucose load (p < 0.05). In normoglycemic rats, repeated administration over 21 days led to a dose-dependent and statistically significant reduction in fasting blood glucose beginning on day 14 and sustained through day 21 (p < 0.01). In diabetic rats, fasting blood glucose levels were significantly reduced from day 7 onward, with 400 mg/kg producing effects comparable to glibenclamide by day 28 (p < 0.01). Insulin, GLUT4, and HbA1c levels were not significantly altered (p > 0.05). Haematological and biochemical parameters remained within normal ranges, and histopathological examination showed preservation of pancreatic and renal tissues in treated groups.

Conclusion: Sclerocarya birrea leaf extract significantly lowers blood glucose in both normoglycemic and diabetic rats without adverse effects, supporting its potential as a safe plant-based option for diabetes management. Further research is warranted to clarify its mechanisms and long-term impact.

Background: Insulin resistance (IR) is a condition where the body cannot respond properly to insulin, leading to elevated blood glucose and the development of type 2 diabetes mellitus (T2DM). The first-line anti-T2DM drug is metformin, however, it has shown adverse effects, challenging the search for alternative natural drugs. Plant flavonoids stimulate cellular glucose uptake, decrease hyperglycemia, and regulate key signaling pathways in glucose metabolism. Brebes shallots (Allium ascalonicum L.) are known to contain flavonoids and thus may have the potential to inhibit IR.

Purpose: To evaluate the effects of the ethanol extract of Brebes shallots in improving IR conditions.

Methods: Brebes shallots were collected from West Java, Indonesia. 500 g of the shallots were oven-dried and extracted using 70% ethanol for 3×24 h, the solvent was evaporated to a thick consistency, and the extract was abbreviated as EAA. The effects of EAA were studied in high-fat-high-fructose (HFHF)-induced Swiss-Webster male mice by performing the insulin tolerance test (ITT) and oral glucose tolerance test (OGTT), and the liver and pancreas index. The nutritional composition and quercetin levels in the extract were also determined.

Results: The extraction process yielded a 28.1% EAA. EAA reduces % weight gain, blood glucose levels in OGTT, and liver and pancreas index. EAA significantly improved insulin tolerance in the HFHF-induced mice (p < 0.05). Proximate analysis resulted in 3.92% ash, 0.12% fat, 13.45% protein, and 60.69% carbohydrate, while quercetin was at 0.0065%.

Conclusion: Allium ascalonicum L. extract may improve IR conditions as confirmed by its ability to increase the ITT value and reduce blood glucose levels. However, further studies are needed to confirm its role in alleviating metabolic disorders.

Introduction: Storage of nutrient energy from a meal is partitioned in the body approximately equally by insulin (with its known actions on the liver and adipose tissue) and hepatalin (released from the liver with its glycogenic action selectively in skeletal muscle, heart, and kidneys). During healthy pregnancy, there is a late stage mixed insulin resistance involving both insulin and hepatalin. In pregnant rats on a high sucrose diet, hepatalin-dependent insulin resistance (HDIR) develops with unaffected direct insulin action. Compensatory hyperinsulinemia maintains blood glucose level with resultant hypertriglyceridemia and adiposity. Previously, in male Sprague Dawley sucrose-supplemented rats, aged for one year, HDIR and the associated cardiometabolic consequences were prevented by using a targeted synergistic antioxidant cocktail composed of S-Adenosyl-Methionine, vitamin E and vitamin C (SAMEC). The current study tested the hypothesis that SAMEC would confer protection against sucrose-induced HDIR in virgin and pregnant rats.

Methods: Post-prandial insulin sensitivity was quantified using the rapid insulin sensitivity test (RIST). Sucrose supplementation (35% sucrose in water) was used to induce HDIR in female rats. Eight weeks of normal or SAMEC diet with or without sucrose supplementation was used as an intervention to determine the extent of protection against HDIR by SAMEC in virgin and pregnant rats.

Results and discussion: SAMEC administered with the sucrose diet prevented the development of HDIR resulting in normal plasma glucose, insulin, and triglyceride concentrations in both virgin and pregnant groups, and attenuated sucrose-induced fat mass gain in virgin rats. The direct insulin action was unimpaired.

Conclusion: SAMEC preserves hepatalin-dependent glucose uptake in virgin and pregnant rats on sucrose supplementation, thus can be used as a preventative in obesity and gestational diabetes.

Purpose: The objective was to verify the impact of the solvent and the harvesting site on the content of phenolic compounds as well as the in vitro antidiabetic activity of leafy stems and roots of Phyllanthus amarus.

Methods: The polyphenols and total flavonoids were measured on the crude extracts, obtained after maceration for 48 hours with acetone-water 50:50 (v/v), and ethanol-water 70:30 (v/v) . These extracts were evaluated for their antioxidant properties by DPPH, ABTS, and iron reduction (FRAP) tests. Finally, the α-amylase inhibitory activity of the crude extracts was determined by the method using DNS.

Results: The results show that acetone-water favors polyphenol extraction, with a maximum content of 32.62 ± 0.85 mg EAG/100 mg DE in leafy stems from Banfora (LSBaAw). In contrast, ethanol-water extracted more flavonoids, with 4.59 ± 0.02 mg EQ/100 mg DE in roots from Bobo (RBoEw). For antioxidant activity, the ethanol-water extract of Bobo leafy stems (LSBoEw) showed the highest ABTS free radical scavenging activity (81.34 ± 1.07 µg/mL). In comparison, the ethanol-water extract of Banfora roots (RBaEw) showed the best DPPH free radical scavenging activity (55.71 ± 2.48 µg/mL). On the other hand, the acetone-water extract of Banfora leafy stems (LSBaAw) showed the highest iron reduction activity (15,445.81 ± 835.75 µmol EAA/100 mg DE). Finally, the highest α-amylase inhibitory activity was observed with ethanol-water extracts from roots (RBaEw: 98.45 ± 0.38%; RBoEw: 96.56±0.31%).

Conclusion: These results underline the importance of the choice of solvent, organ, and harvesting site in optimizing the use of Phyllanthus amarus. Further studies involving other solvents and environmental conditions will enable us to refine these observations and optimize the pharmacological potential of this plant.